The developmental and evolutionary characteristics of transcription factor binding site clustered regions based on an explainable machine learning model.

Gene expression is temporally and spatially regulated by the interaction of transcription factors (TFs) and cis-regulatory elements (CREs). The uneven distribution of TF binding sites across the genome poses challenges in understanding how this distribution evolves to regulate spatio-temporal gene expression and consequent heritable phenotypic variation. In this study, chromatin accessibility profiles and gene expression profiles were collected from several species including mammals (human, mouse, bovine), fish (zebrafish and medaka), and chicken. Transcription factor binding sites clustered regions (TFCRs) at different embryonic stages were characterized to investigate regulatory evolution. The study revealed dynamic changes in TFCR distribution during embryonic development and species evolution. The synchronization between TFCR complexity and gene expression was assessed across species using RegulatoryScore. Additionally, an explainable machine learning model highlighted the importance of the distance between TFCR and promoter in the coordinated regulation of TFCRs on gene expression. Our results revealed the developmental and evolutionary dynamics of TFCRs during embryonic development from fish, chicken to mammals. These data provide valuable resources for exploring the relationship between transcriptional regulation and phenotypic differences during embryonic development.

Developmental toxicity and mechanism of dibutyl phthalate and alternative diisobutyl phthalate in the early life stages of zebrafish (Danio rerio).

Diisobutyl phthalate (DiBP), is widely chemical replacement for Dibutyl phthalate (DBP). Although DBP and DiBP have been detected in surface water worldwide, few studies to date have systematically assessed the risks of DBP and its alternatives to aquatic organisms. The present study compared DBP and DiBP for their individual and joint toxicity as well as thyroid hormone levels in zebrafish embryo. Transcripts of key genes related to the hypothalamic-pituitary-thyroid (HPT) axis were investigated in developing zebrafish larvae by application of real time polymerase chain reaction. The median half-lethal concentrations of DBP and DiBP to zebrafish at 96 h were 0.545 mg L-1 and 1.149 mg L-1, respectively. The joint toxic effect of DBP-DiBP (0.25-0.53 mg L-1) with the same ratio showed a synergistic effect. Thyroid hormones levels increased with exposure to 10 µg L-1 of DBP or 50 µg L-1 of DiBP, and exposure to both compounds significantly increased thyroid gland-specific transcription of thyroglobulin gene (tg), hyronine deiodinase (dio2), and transthyretin (ttr), indicating an adverse effect associated with the HPT axis. Molecular docking results indicated that DBP (-7.10 kcal/M and -7.53 kcal/M) and DiBP (-6.63 kcal/M and -7.42 kcal/M) had the same docking energy with thyroid hormone receptors. Our data facilities an understand of potential harmful effects of DBP and its alternative (DiBP).

Phthalic acid esters: Are they a big concern for rivers flowing into reservoir with ecological facilities?

The city-river-reservoir system is an important system for safeguarding drinking water. Phthalic acid esters (PAEs) are emerging contaminants in drinking water sources that are gaining attention, and they could pose risks to human health and aquatic organisms. In this study, field studies that lasted four years were conducted to analyze the concentrations, spatial-temporal distribution, and removal effects of six PAEs. The total concentrations of the Σ6PAEs in the water and sediment samples were 0.2-7.4 µg L-1 (mean: 1.3 µg L-1) and 9.2-9594.1 ng g-1 (mean: 847.5 ng g-1), respectively. Di-n-butyl phthalate (DBP) and, bis(2-ethylhexyl) phthalate (DEHP) were the predominant congeners, accounting for 57.2 % in the water samples and 94.1 % in the sediment samples. The urban area contributed 72 % of the PAEs in the system. A significant removal effect of PAEs was observed in the wetland, with a removal rate of 40.2 %. The partitioning of PAEs between the water and sediment was attributed to the removal of dimethyl phthalate and diethyl phthalate that occurred during the water phase, while the removal of DBP and DEHP primarily occurred during the sediment phase. The ecological risk calculation based on the sensitivity distribution model indicated that DBP (HQwater = 0.19, HQsediment = 0.46) and DEHP (HQwater = 0.20, HQsediment = 0.13) possessed moderate risks according to some water and sediment samples. The ecological projects were verified to be effective engineering strategies to reduce ecological risk in the drinking water source.

Erratum: CD31 promotes diffuse large B-cell lymphoma metastasis by upregulating OPN through the AKT pathway and inhibiting CD8+ T cells through the mTOR pathway.

[This corrects the article on p. 2656 in vol. 15, PMID: 37193155.].

The anti-cholestatic effects of Coptis chinensis Franch. alone and combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley: dual effects on fecal metabolism and microbial diversity.

Introduction: Drug dosages and combinations are the main factors that affect the efficacy of pleiotropic traditional Chinese medicine (TCM). Coptis chinensis Franch. (CF) is a representative TCM with multiple effects and is often combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley (TR) to treat cholestasis. The present study assessed the influence of CF dose and its combination with TR on the efficacy of CF in cholestasis treatment, including their effects on fecal metabolism and fecal microorganisms. Methods: Rats with α-naphthylisothiocyanate (ANIT, 50 mg/kg)-induced cholestasis were administered low (0.3 g/kg) and high (0.6 g/kg) doses of CF, as well as CF combined with TR at doses of 0.6 g/kg and 0.9 g/kg, respectively. The anti-cholestatic effects of these treatments were assessed by determining their anti-inflammatory, hypolipidemic, and anti-oxidative stress properties. Additionally, fecal metabolomics and fecal microorganisms were analyzed. Results: Low dose CF had a more potent hypolipidemic effect than high dose CF, whereas high dose CF had more potent anti-inflammatory and anti-oxidative stress effects. Combination with TR enhanced the hypolipidemic effect, but antagonized the anti-inflammatory effect, of CF. Analyses of fecal metabolomics and fecal microorganisms showed differences in the regulation of lipid- and amino acid metabolism-related pathways, including pathways of linoleic acid, tyrosine, and arachidonic acid metabolism, and amino acid biosynthesis between different doses of CF as well as between different doses of CF in combination with TR. These differences may contribute to differences in the anti-cholestatic effects of these preparations. Conclusion: CF dose influences its anti-cholestatic efficacy. The combination with TR had synergistic or antagonistic effects on the properties of CF, perhaps by altering fecal metabolism and fecal microbial homeostasis.

Biological Control of Avocado Branch Blight Caused by Lasiodiplodia theobromae Using Bacillus velezensis.

In recent years, avocado branch blight has gradually become one of the major diseases causing mortality of avocado trees, which seriously affects the economic development of avocado planting regions. In order to investigate the cause of the disease, the pathogens were isolated from the interroot of avocado trees with the onset of the disease and identified as Lasiodiplodia theobromae. At the same time, three Bacillus velezensis strains, YK194, YK201, and YK268, with better antagonistic effects and high stability against L. theobromae, were isolated from the rhizospheric soil of healthy avocado plants. The results of branch experiments and field trials showed that the avocado leaves as well as branches treated with the strains YK194, YK201, and YK268 did not develop disease, and the incidence of avocado trees was significantly reduced. In the branch experiments, the biological control effect of the strains YK194, YK201, and YK268 reached 62.07, 52.70, and 72.45%, respectively. In the field experiments, it reached 63.85, 63.43, and 73.86%, respectively, which indicated that all these three strains possessed good biological control effects on avocado branch blight. Further investigation on the mechanism of action of antagonistic strains revealed that B. velezensis YK268 could produce lipopeptides, namely, surfactin, fengycin, and iturin, which could significantly inhibit the spore germination of L. theobromae. Consequently, these three isolates have potential as biocontrol agents against L. theobromae.

Sonographic Findings of Vascular Signals for Retained Products of Conception in Women Following First-Trimester Termination of Pregnancy.

OBJECTIVES: To evaluate the occurrence of retained products of conception (RPOC) after termination of pregnancy in the first trimester and to assess the vascular signals with transvaginal ultrasonography (TVUS) examination in the detection of retained products. METHODS: A retrospective cohort study was performed using TVUS examination in patients following termination of pregnancy. In cases of RPOC, 3 scales of vascular signal were identified: type 1, no or small amount, spot flow signals; type 2, medium amount, strip-like flow signals; type 3, rich amount, circumferential-like flow signals. The correlation between vascular signals and placenta accreta spectrum (PAS) staging was proposed by sonography and histopathology findings. RESULTS: The 3 vascular patterns were differently distributed within non-RPOC as well as RPOC patients with and without PAS: type 1 vascular signal detection rates of non-RPOC and RPOC were 97.8% (262/268) and 28.1% (18/64), respectively. Of 64 cases of RPOC, 48.4% (31/64) of the patients had type 2 vascular signals. Vascular signals were enhanced in RPOC with PAS patients whose diagnosis was confirmed by histopathology. CONCLUSIONS: The vascularity (amount of flow), vascular pattern (spot, strip- or circumferential-like flow), and the flow penetrating myometrium were significant findings for distinguishing concomitant RPOC with and without PAS. Additionally, RPOC may contribute to PAS progression, or PAS and RPOC in coordination strengthen the observed vascular signals.

Biological control of potato common scab and growth promotion of potato by Bacillus velezensis Y6.

Potato common scab, caused mainly by Streptomyces scabies, causes surface necrosis and reduces the economic value of potato tubers, but effective chemical control is still lacking. In this study, an attempt was made to control potato common scab by inoculating potatoes with Bacillus velezensis (B. velezensis) and to further investigate the mechanism of biological control. The results showed that B. velezensis Y6 could reduce the disease severity of potato common scab from 49.92 ± 25.74% [inoculated with Streptomyces scabies (S. scabies) only] to 5.56 ± 1.89% (inoculated with S. scabies and Y6 on the same day) and increase the potato yield by 37.32% compared with the control under pot experiment in this study. Moreover, in the field trial, it was found that Y6 could also significantly reduce disease severity from 13.20 ± 1.00% to 4.00 ± 0.70% and increase the potato yield from 2.07 ± 0.10 ton/mu to 2.87 ± 0.28 ton/mu (p < 0.01; Tukey's test). Furthermore, RNA-seq analysis indicated that 256 potato genes were upregulated and 183 potato genes were downregulated in response to B. velezensis Y6 inoculation. In addition, strain Y6 was found to induce the expression of plant growth-related genes in potato, including cell wall organization, biogenesis, brassinosteroid biosynthesis, and plant hormone transduction genes, by 1.01-4.29 times. As well as up-regulate hydroquinone metabolism-related genes and several transcription factors (bHLH, MYB, and NAC) by 1.13-4.21 times. In summary, our study will help to understand the molecular mechanism of biological control of potato common scab and improve potato yield.

Joint association of sleep duration and physical activity with cognitive performance among Chinese adults: an analysis of nationally representative survey data.

Background: Although previous studies have identified that both physical activity and sleep problems are independently associated with decreased risk of cognitive function. However, the joint association of physical activity and sleep duration with cognitive function was rarely studied. Methods: A total of 21,128 participants who had records from the China Family Panel Studies (CFPS) in 2018 were included in this study. Linear regression was used to examine the associations of joint between physical activity and sleep duration with cognitive function in the nationally representative survey data. Results: Compared with individuals reporting 150 min/week or more of activity, those reporting no physical activity had a 116% higher risk of getting lower vocabulary scores (coefficient: -1.16, 95% CI: -1.55 ~ -0.78) and a 61% higher risk of getting lower mathematics scores (coefficient: -0.61, 95% CI: -0.78 ~ -0.44). Compared with those who slept for 7-10 h/day, those who slept more than 10 h/day had the lower vocabulary scores (coefficient: -1.34, 95% CI: -1.86 ~ -0.83) and mathematics scores (coefficient: -0.68, -0.94 ~ -0.42). The results of joint analysis showed that the adjusted coefficient for vocabulary scores were - 2.58 (95% CI, -3.33 ~ -1.82) for individuals reporting no physical activity and sleeping for 10 h/day, and - 1.00 (95% CI, -1.88 ~ -0.12) for individuals reporting more than 150 min/week and sleeping for 10 h/day, compared with those who reported a sleep duration for 7-10 h/day and more than 150 min/week physical activity, Any level of physical activity combined with longer sleep duration (≥10 h/day) was associated with a higher risk of getting low mathematics scores. Conclusion: Appropriate sleep and sufficient physical activity together may have amplified association on cognitive performance, highlighting the importance of a comprehensive healthy lifestyle.

The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes.

Background: The Zhuyu pill (ZYP), composed of Coptis chinensis Franch. and Tetradium ruticarpum (A. Jussieu) T. G. Hartley, is an effective traditional Chinese medicine with potential anti-cholestatic effects. However, the underlying mechanisms of ZYP remain unknown. Objective: To investigate the mechanism underlying the interventional effect of ZYP on mRNA-seq analysis in cholestasis rat models. Materials and methods: This study tested the effects of a low-dose (0.6 g/kg) and high-dose (1.2 g/kg) of ZYP on a cholestasis rat model induced by α-naphthyl-isothiocyanate (ANIT, 50 mg/kg). Serum biochemistry and histopathology results were used to evaluate the therapeutic effect of ZYP, and mRNA-Seq analysis was performed and verified using real-time fluorescence quantitative PCR (qRT-PCR). GO, KEGG, and GSEA analyses were integrated to identify the mechanism by which ZYP impacted cholestatic rats. Results: ZYP was shown to significantly improve abnormal changes in the biochemical blood indexes and liver histopathology of cholestasis rats and regulate pathways related to bile and lipid metabolism, including fatty acid metabolism, retinol metabolism, and steroid hormone biosynthesis, to alleviate inflammation, cholestasis, and lipid metabolism disorders. Relative expression of the essential genes Cyp2a1, Ephx2, Acox2, Cyp1a2, Cyp2c11, and Sult2a1 was verified by qRT-PCR and showed the same trend as mRNA-seq analysis. Conclusion: ZYP has a significant anti-cholestatic effect by regulating bile metabolism and lipid metabolism related pathways. These findings indicate that ZYP is a novel and promising prospect for treating cholestasis.

Artesunate synergistically promotes sorafenib­induced apoptosis and ferroptosis in non­Hodgkin lymphoma cells through inhibition of the STAT3 pathway.

Despite the development of advanced therapies, the prognosis of non­Hodgkin lymphoma (NHL) remains unsatisfactory due to refractory and relapsed cases. Artesunate (ART) and sorafenib (SOR) both exert potential antitumor activity in lymphoma. The present study aimed to investigate whether ART and SOR produce synergistic anti­lymphoma effects, and to determine the potential underlying mechanisms. Cell viability assay, flow cytometry, malondialdehyde assay, GSH assay and western blotting were performed to evaluate cell viability, and changes in apoptosis, autophagic vacuoles, reactive oxygen species, mitochondrial membrane potential, lipid peroxidation and protein expression. The results demonstrated that ART and SOR synergistically inhibited the viability of NHL cells. ART and SOR also synergistically induced apoptosis, and markedly increased the expression levels of cleaved caspase­3 and poly (ADP­ribose) polymerase. Mechanistically, ART and SOR synergistically induced autophagy, and rapamycin enhanced the ART­ or SOR­induced inhibition of cell viability. Furthermore, it was demonstrated that ferroptosis promoted ART­ and SOR­induced cell death through increasing lipid peroxides. Erastin enhanced the inhibitory effects of ART and SOR on cell viability, whereas ferrostatin­1 reduced the ART­ and SOR­induced apoptosis of SU­DHL4 cells. Further studies revealed that signal transducer and activator of transcription 3 (STAT3) contributed to ferroptosis induced by ART and SOR in NHL cells, and genetic inhibition of STAT3 promoted ART/SOR­induced ferroptosis and apoptosis, concomitantly reducing the expression levels of glutathione peroxidase 4 and myeloid cell leukemia­1. Moreover, the combined treatment of ART and SOR exerted inhibitory effects on tumor growth, as well as antiangiogenic activity, resulting in the inhibition of CD31 expression in a xenograft model. Collectively, these findings indicated that ART acted synergistically with SOR to inhibit cell viability, and to induce apoptosis and ferroptosis through regulating the STAT3 pathway in NHL. Notably, ART and SOR may act as potential therapeutic agents for the treatment of lymphoma.

HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy.

Epidemiologic studies detected an inverse relationship between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major risk factor for ASCVD and suggesting atheroprotective functions of HDL. However, the role of HDL-C as a mediator of risk for ASCVD has been called into question by the failure of HDL-C-raising drugs to reduce cardiovascular events in clinical trials. Progress in understanding the heterogeneous nature of HDL particles in terms of their protein, lipid, and small RNA composition has contributed to the realization that HDL-C levels do not necessarily reflect HDL function. The most examined atheroprotective function of HDL is reverse cholesterol transport, whereby HDL removes cholesterol from plaque macrophage foam cells and delivers it to the liver for processing and excretion into bile. Indeed, in several studies, HDL has shown inverse associations between HDL cholesterol efflux capacity and ASCVD in humans. Inflammation plays a key role in the pathogenesis of atherosclerosis and vulnerable plaque formation, and a fundamental function of HDL is suppression of inflammatory signaling in macrophages and other cells. Oxidation is also a critical process to ASCVD in promoting atherogenic oxidative modifications of LDL (low-density lipoprotein) and cellular inflammation. HDL and its proteins including apoAI (apolipoprotein AI) and PON1 (paraoxonase 1) prevent cellular oxidative stress and LDL modifications. Importantly, HDL in humans with ASCVD is oxidatively modified rendering HDL dysfunctional and proinflammatory. Modification of HDL with reactive carbonyl species, such as malondialdehyde and isolevuglandins, dramatically impairs the antiatherogenic functions of HDL. Importantly, treatment of murine models of atherosclerosis with scavengers of reactive dicarbonyls improves HDL function and reduces systemic inflammation, atherosclerosis development, and features of plaque instability. Here, we discuss the HDL antiatherogenic functions in relation to oxidative modifications and the potential of reactive dicarbonyl scavengers as a therapeutic approach for ASCVD.

CD31 promotes diffuse large B-cell lymphoma metastasis by upregulating OPN through the AKT pathway and inhibiting CD8+ T cells through the mTOR pathway.

OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin's lymphoma. Invasive DLBCL cells are likely to metastasize into extranodal tissue (e.g., the central nervous system) that is difficult for chemotherapy drugs to penetrate, seriously affecting patient prognosis. The mechanism of DLBCL invasion remains unclear. This study investigated the association between invasiveness and platelet endothelial cell adhesion molecule-1 (CD31) in DLBCL. METHODS: This study consisted of 40 newly diagnosed DLBCL patients. Differentially expressed genes and pathways in invasive DLBCL cells were identified using real-time polymerase chain reaction, western blotting, immunofluorescence, and immunohistochemical staining, RNA sequencing, and animal experiments. The effect of CD31-overexpressing DLBCL cells on the interactions between endothelial cells was determined using scanning electron microscopy. The interactions between CD8+ T cells and DLBCL cells were examined using xenograft models and single-cell RNA sequencing. RESULTS: CD31 was upregulated in patients with multiple metastatic tumor foci compared to patients with a single tumor focus. CD31-overexpressing DLBCL cells formed more metastatic foci in mice and shortened mouse survival time. CD31 disrupted the tight junctions between endothelial cells of the blood-brain barrier by activating the osteopontin-epidermal growth factor receptor-tight junction protein 1/tight junction protein-2 axis through the protein kinase B (AKT) pathway, enabling DLBCL to enter the central nervous system to form central nervous system lymphoma. Furthermore, CD31-overexpressing DLBCL cells recruited CD31+ CD8+ T cells that failed to synthesize interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), and perforin via the activated mTOR pathway. Some target genes, such as those encoding S100 calcium-binding protein A4, macrophage-activating factor, and class I b-tubulin, may be used to treat this type of DLBCL surrounded by functionally suppressed CD31+ memory T cells. CONCLUSIONS: Our study suggests that DLBCL invasion is associated with CD31. The presence of CD31 in DLBCL lesions could represent a valuable target for treating central nervous system lymphoma and restoring CD8+ T-cell function.

A graph neural network-based interpretable framework reveals a novel DNA fragility-associated chromatin structural unit.

BACKGROUND: DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, and they can cause cancer if improperly repaired. Recent chromosome conformation capture techniques, such as Hi-C, have enabled the identification of relationships between the 3D chromatin structure and DSBs, but little is known about how to explain these relationships, especially from global contact maps, or their contributions to DSB formation. RESULTS: Here, we propose a framework that integrates graph neural network (GNN) to unravel the relationship between 3D chromatin structure and DSBs using an advanced interpretable technique GNNExplainer. We identify a new chromatin structural unit named the DNA fragility-associated chromatin interaction network (FaCIN). FaCIN is a bottleneck-like structure, and it helps to reveal a universal form of how the fragility of a piece of DNA might be affected by the whole genome through chromatin interactions. Moreover, we demonstrate that neck interactions in FaCIN can serve as chromatin structural determinants of DSB formation. CONCLUSIONS: Our study provides a more systematic and refined view enabling a better understanding of the mechanisms of DSB formation under the context of the 3D genome.

Three-dimensional distribution characteristics of multiple pollutants in the soil at a steelworks mega-site based on multi-source information.

Soil pollution at steelworks mega-sites has become a severe environmental issue worldwide. However, due to the complex production processes and hydrogeology, the soil pollution distribution at steelworks is still unclear. This study scientifically cognized the distribution characteristics of polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and heavy metals (HMs) at a steelworks mega-site based on multi-source information. Specifically, firstly, 3D distribution and spatial autocorrelation of pollutants were obtained by interpolation model and local indicators of spatial associations (LISA), respectively. Secondly, the characteristics of horizontal distribution, vertical distribution, and spatial autocorrelations of pollutants were identified by combining multi-source information such as production processes, soil layers, and properties of pollutants. Horizontal distribution showed that soil pollution in steelworks mainly occurred in the front end of the steel process chain. Over 47% of PAHs and VOCs pollution area were distributed in coking plants and over 69% of HMs in stockyards. Vertical distribution indicated that HMs, PAHs, and VOCs were enriched in the fill, silt, and clay layers, respectively. Spatial autocorrelation of pollutants was positively correlated with their mobility. This study clarified the soil pollution characteristics at steelworks mega-sites, which can support the investigation and remediation of steelworks mega-sites.

Tumor-Derived Oxidative Stress Triggers Ovarian Follicle Loss in Breast Cancer.

Breast cancer is a common indication for ovarian cryopreservation. However, whether the grafting ovarian tissue meets functional requirements, as well as the need for additional interventions, remains unclear. The current study demonstrates abnormal serum hormones in breast cancer in humans and breast cancer cell line-derived tumor-bearing mice, and for the first time shows tumor-induced loss of primordial and growing follicles, and the number of follicles being lost to either growth or atresia. A gene signature of tumor-bearing mice demonstrates the disturbed regulatory network of steroidogenesis, which links to mitochondria dysfunction in oocytes and granulosa cells via the phosphatidylinositol 3-kinase signaling pathway. Notably, increased reactive oxygen species were identified in serum and ovarian tissues in tumor-bearing mice. Furthermore, supplementation with vitamin C promoted follicular quiescence, repairing tumor-induced follicle loss via inactivation of the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, indicating the potential of antioxidants as a fertility therapy to achieve higher numbers of healthy follicles ready for ovarian cryopreservation.

Scavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance.

OBJECTIVE: Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5'-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr-/- mice. METHODS: Male or female Ldlr-/- mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2'-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge. RESULTS: PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr-/- mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr-/- mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr-/- mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr-/- mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1ß expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr-/- mice. CONCLUSIONS: PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.

The Role of Macrophages and Alveolar Epithelial Cells in the Development of ARDS.

Acute lung injury (ALI) usually causes acute respiratory distress syndrome (ARDS), or even death in critical ill patients. Immune cell infiltration in inflamed lungs is an important hallmark of ARDS. Macrophages are a type of immune cell that participate in the entire pathogenic trajectory of ARDS and most prominently via their interactions with lung alveolar epithelial cells (AECs). In the early stage of ARDS, classically activated macrophages secrete pro-inflammatory cytokines to clearance of the pathogens which may damage alveolar AECs cell structure and result in cell death. Paradoxically, in late stage of ARDS, anti-inflammatory cytokines secreted by alternatively activated macrophages dampen the inflammation response and promote epithelial regeneration and alveolar structure remodeling. In this review, we discuss the important role of macrophages and AECs in the progression of ARDS.

Metagenomic Next-Generation Sequencing (mNGS) for the Timely Diagnosis of Carbapenem-Resistant Klebsiella pneumoniae in Leukemia Patients.

This report shows the contribution of metagenomic next-generation sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report two leukemia patients who developed severe infections due to carbapenem-resistant Klebsiella pneumoniae (CrKP). The mNGS can be strongly recommended as an alternative investigation for patients who are at high risk of infection without positivity on body fluid culture. This can provide the opportunity for adequate therapy.